Revision ICH Q1
Practical Implementation and Lifecycle Stability Studies – Impact of the ICH Q1 Revision: “Guideline on Stability Testing of Drug Substances and Drug Products”
Evaluating product quality—and changes therein—over time under the influence of detrimental environmental factors such as temperature, humidity, and light is an essential requirement of quality control.
The revision of the core ICH Q1 guideline has aligned this task with the current state of scientific knowledge and regulatory requirements, thereby redefining the specifications for conducting stability studies.
The new version of the guideline will replace and consolidate the previous guidelines Q1A–F and Q5c. Contrary to what the title might suggest, the scope is not limited to active substances and finished products; in fact, the revision has significantly expanded the range of “product classes” covered. Stability studies are now explicitly required for new excipients, reference standards, intermediates, combination products (drug substance/finished product + medical device), vaccine adjuvants, and co-packaged solvents or diluents.
Updated requirements have also been introduced for advanced therapy medicinal products (ATMPs), as well as for synthetic and biological active substances and finished products.
The guideline significantly expands the scope of activities required throughout the product lifecycle (from development to marketing authorization) and places greater emphasis on the necessity of “forced degradation” and “stress studies.” Stability data must be available for the entire lifecycle. Activities during the early stages of product development are particularly crucial for building the product knowledge required by regulatory authorities.
The guiding principle here is: “Stability is not the result of stability studies, but of competent product development”
Critical stability characteristics of the product must be identified at an early stage and used to inform the development process. “Exploratory stress studies” thus yield the critical quality attributes (CQAs) that largely determine the subsequent scope of testing and the stability-indicating capabilities of the analytical methods. Moreover, they provide valuable insights for formulation development, packaging optimization regarding protection against environmental factors, and preliminary indications regarding shelf life and suitable transport conditions.
The inclusion of intermediates means that hold times and processing times (bulk stability) are now also relevant factors.
For combination products, the suitability of the medical device component and its compatibility with the formulation or active substance are assessed. As with medicinal products (active substance plus excipients), the stability of a combination product cannot necessarily be concluded from the intrinsic stability of its individual components; a stability study of the finished product is mandatory. This requires demonstrating both the stability of the product itself and the functionality of the medical device component. The shelf life of the combination product is determined by the component with the shortest shelf life.
Nevertheless, understanding the properties of the individual components and the potential formation of toxic by-products is crucial for anticipating the behavior of the finished product. The guideline explicitly mentions the assessment of toxic by-products, such as nitrosamines. Another new requirement is the collection of stability data for reference standards if they have not been obtained from commercial sources
There are only minor changes regarding the formally required registration studies, ongoing stability studies, and studies conducted following post-approval changes (PAC). It is worth noting that the option to replace the 30°C/35% RH climatic condition with 30°C/65% RH for studies involving semi-permeable packaging has been removed.
The chapter defining the minimum requirements for initial registration studies has been updated. Data from three batches are required, covering 6 or 12 months of long-term testing and 6 months of accelerated testing. The new guideline provides no specific requirements for determining the scope of studies following changes (PAC); instead, as is often the case, it refers to an individual risk analysis.
Options for reducing the stability study design have been better explained and expanded upon. Annex 3 outlines concepts for matrixing and bracketing, while Annex 2 describes the potential use of stability modeling. However, simple extrapolation is no longer sufficient to characterize stability behavior; robust statistical models for analyzing stability data must be submitted to justify reducing the scope of the studies.
